Elimination of cocaine by pregnant sheep following single or multiple exposures.

To test the hypothesis that chronic exposure to cocaine would alter drug elimination in pregnant and fetal sheep compared to a single exposure, we administered intravenous cocaine HCl to 8 pregnant sheep daily as a bolus, followed by a 2-h infusion beginning at gestational age 75 days. Eight additional animals received an equivalent volume of saline. Three days after maternal and fetal catheter placement on day 125, ewes in both groups received cocaine HCl, 2 mg/kg, as a bolus. Maternal and fetal plasma samples were serially obtained and analyzed for cocaine and benzoylecognine. Cocaine half-life in the ewes and fetuses exposed to cocaine was no different from that in animals exposed to saline. We conclude that cocaine is rapidly metabolized in pregnant sheep and that chronic administration does not alter drug clearance.

Cocaine depresses cerebral glucose utilization in fetal sheep.

To assess if cocaine alters cerebral glucose metabolism in the fetus, we infused cocaine 0.6 mg/min intravenously to 6 of 13 fetal sheep for the 55 min prior to measurement of glucose utilization by an autoradiographic method. Overall, local cerebral glucose utilization (LCGU) was lower in cocaine-exposed fetuses than in 7 controls (P = 0.058). In the cocaine-exposed fetuses, 33 of 34 structures had lower mean LCGU than in the comparable structures of control fetuses. In addition, the autoradiographs in 4 of 6 cocaine-exposed fetuses revealed thin, dark lines of increased glucose utilization within the central white matter of some frontal gyri which were not seen in any of the 7 control fetuses. These lines were distributed similarly to ones seen earlier in severely hypoxic newborn lambs. In fetal lambs, cocaine resulted in a generalized decrease in LCGU and a specific increase in glucose utilization in parts of cortical white matter of the frontal gyri, possibly secondary to local ischemia.

Local cerebral glucose utilization in normoxemic and hypoxemic newborn lambs.

To determine if hypoxemia altered local cerebral glucose utilization (LCGU) in newborn lambs, and where these alterations occurred, we measured LCGU using the 2-[14C]deoxyglucose [( 14C]DG) autoradiographic technique in lambs made hypoxemic by gradual reduction in inspired oxygen concentration. In 5 normoxemic control lambs, aged 3 days. LCGU of the cerebral cortex and white matter was higher than published values of LCGU in similar structures in near term normal fetuses and 2-4 times higher than reported values in normoxemic puppies. LCGU was highest in vestibular nuclei and auditory structures, followed by cerebellar nuclei, cerebral subcortical structures, and white matter. In 6 hypoxemic newborn lambs (paO2 14-18 torr) consistent increases in LCGU were noted only in the corona radiata compared to the values obtained in the normoxemic control lambs (36.5 +/- 8.1 vs. 23.9 +/- 1.7 mumol/100 per min, mean +/- S.D., P less than 0.02). This increase in LCGU in white matter was clearly noted in autoradiographs in which thin dark central regions within white matter often reached high into the gyri. In the hypoxic group. LCGU of the corona radiata superseded the value in many gray matter structures. In addition, patchy increases of [14C]DG utilization were present in the cerebral cortex of two hypoxemic lambs. Acute hypoxemia increases glucose utilization of the corona radiata to values equivalent to many gray matter structures, and leads to heterogeneous glucose metabolism in the cerebral cortex, but does not alter LCGU in other gray matter structures of newborn sheep.

Cocaine alters behavioral states in fetal sheep.

Intrauterine cocaine exposure causes subtle neurologic abnormalities in human newborn infants; however, the mechanism for these abnormalities is not known. To investigate whether cocaine alters fetal behavioral state, the electrocortical, electro-ocular and neck muscle electrical activity was monitored in 7 chronically instrumented fetal sheep before and during both saline and cocaine HCl infusions directly to the fetus. Saline infusion to the fetus had no effect on the percentage of time spent in rapid eye movement sleep compared to no infusion (37.5 +/- 11.6% vs 46.3 +/- 4.6%, mean +/- SD, P greater than 0.1). Cocaine infusion directly to the fetus had no effect on fetal arterial pO2, but did increase mean arterial pressure from 53.6 +/- 15 mmHg to 61.0 +/- 21 mmHg (P less than 0.01). In addition, during cocaine infusion, the percentage of time spent in rapid eye movement sleep dropped to 3.9 +/- 5.1% (P less than 0.0001) and the average duration of rapid eye movement epochs decreased from 10.1 +/- 3.0 min precocaine infusion to 1.9 +/- 2.6 min during cocaine infusion (P less than 0.02). The influence of cocaine was noted in a frequency analysis of the electrocorticogram. The amplitude of the energy centered at 1 Hz during cocaine infusion (73.8 +/- 4.0 dB) was greater than the amplitude during rapid eye movement sleep (65.5 +/- 4.7 dB) and less than the amplitude during non-rapid eye movement periods (79.9 +/- 4.5 dB) (P = 0.01). Cocaine appears to alter fetal behavioral state directly and this may play a role in the abnormal behavior in newborn infants exposed to cocaine in utero.

Effect of cocaine on electrocortical activity in fetal sheep.

The effect of cocaine on the behavioral state of six fetal sheep was studied during gestational ages between 128-135 days. Two to eight days after surgery, fetuses received either a continuous 60 min intravenous infusion of cocaine HCl (33.4 mg) or saline. The infusions were preceded and followed by control periods of 102 min. Cocaine induced a disruption in fetal behavioral state cyclicity and a decrease in the amount of time spent in rapid eye movement sleep (P < 0.01) and non-rapid eye movement sleep (P < 0.05) during the infusion, but not during the recovery period. Spectral amplitude of the electrocortical activity at all three cortical locations increased within most one-third octave bands between 0.8-4 Hz and decreased within most bands between 16-25 Hz (P < 0.05) compared to controls. There were no differences in spectral amplitude between pre- and post-cocaine periods at any location over the 25 frequency bands studied (P > 0.6) except for one frequency band centered at 12.5 Hz. The effects of a one hour cocaine infusion on fetal cortical electrical activity are diffuse, but short-lived, and occur independently of changes in fetal oxygenation.

The ontogeny of glutamate receptors and D-aspartate binding sites in the ovine CNS.

The ontogeny of ligand binding to N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate (KA) receptors and to the high affinity, sodium-dependent D-aspartate binding site in prenatal and postnatal ovine brains was studied using quantitative in vitro autoradiography. In general, the binding density for each of the excitatory amino acid receptors peaked during late prenatal and early postnatal development. In contrast, binding density for D-aspartate remained low during late prenatal and early postnatal development and peaked in the adult. These data suggest that an excess number of excitatory amino acid receptors and/or a relative deficiency of transporters may make the immature brain more vulnerable to the pathologic effects of glutamate and other related excitatory amino acids.

Carboxy- and oxyhemoglobin in pregnant ewe and fetus after inhalation of marijuana, marijuana placebo and tobacco cigarette smoke.

We measured carboxyhemoglobin (HbCO) and oxyhemoglobin (HbO2) percent saturations and blood gases in four near-term pregnant ewes and their fetuses, during and for 6 hours after 9-12 minutes of smoke inhalation from one high-potency marijuana cigarette (M), a marijuana placebo cigarette (P), and a reference tobacco cigarette (T). Maternal HbCO reached maximum levels at or soon after the exposure (M, 2.8%; P, 3.5%; T, 6.3% above baseline) and fell to baseline values by 6 hours. Fetal HbCO rose slowly reaching a plateau at 3 hours (M, 0.7%; P, 1.1%; T, 2.0% above baseline) which was maintained for at least three additional hours. Reductions in maternal and fetal HbO2 after exposure to marijuana placebo and reference tobacco cigarettes reflected these rises in HbCO. After exposure to marijuana cigarettes, however, fetal HbO2 dropped precipitously by 17% of baseline and showed a prolonged rate of return to presmoking HbO2 levels. Although P exposure caused a greater change in HbCO in the fetus than did M, it had a less-profound effect on fetal oxygenation.

Inhalational administration of cocaine in sheep.

A pipe for administration of inhaled cocaine and its pyrolytic products in laboratory animals was developed and tested. In-vitro trials showed 30.0 +/- 5.2% (mean +/- SE) recovery of cocaine in solvent. Five non-pregnant ewes were instrumented with tracheal T-tubes and vascular catheters. After surgical recovery, ewes received three doses of cocaine (free base) in a randomized fashion; 2 mg/kg and 4 mg/kg both by inhalation, and 2 mg/kg intravenously. Arterial blood samples were collected and assayed for cocaine and its major metabolites by high performance liquid chromatography. Blood pressure and heart rate were continuously recorded. Cocaine administered by inhalation was eliminated with a half-life of 1.6 +/- 0.5 min (mean +/- SE) compared to 3.4 +/- 0.9 following intravenous administration (p less than 0.03). Likewise, clearance values were greater following inhalation, 5532 +/- 1756 ml/min/kg, than following intravenous administration, 163 +/- 20.6 ml/min/kg (p less than 0.04). Both routes of administration led to significant elevations in blood pressure, 7.5% increase after smoking vs 20% increase after intravenous administration. No correlation was found between inhalational dose of cocaine and peak plasma cocaine concentration.

Effects of graded doses of epinephrine during asphxia-induced bradycardia in newborn lambs.

To study the hemodynamic effects of graded doses of epinephrine (EPI) in a newborn animal model of hemodynamically significant bradycardia, we performed the following study. Ten newborn lambs were chronically instrumented with catheters and flow transducers so that systemic, pulmonary arterial, left atrial and right atrial pressures as well as heart rate, cardiac output and left carotid artery flow could be monitored. During each of five asphyxia induced bradycardia episodes, with cardiac output depressed to approximately 30% of baseline, lambs were given either 0, 1, 10, 50, or 100 micrograms of EPI in a randomized sequence. After 30 s, the lambs were resuscitated with room air ventilation while hemodynamic parameters were monitored. During asphyxia and prior to EPI administration, all hemodynamic parameters were similar. In addition, for the first 30 s following EPI administration, hemodynamic parameters continued to deteriorate in a manner that was not influenced by the dose of EPI administered. During the resuscitation period with resumption of ventilation, systemic blood pressure and coronary perfusion pressure rose higher following 50 and 100 micrograms/kg of EPI than after the smaller doses. Heart rate was highest following the 100 micrograms/kg dose. Stroke volume and cardiac output, however, appeared to be blunted by the 100 micrograms/kg dose of EPI with no differences in carotid flow noted by dose of EPI administered. It appears that doses of EPI greater than 10 micrograms/kg, the dose currently recommended by the American Heart Association, may be beneficial as an adjunct in treatment of hemodynamically significant bradycardia. However, doses as high as 100 micrograms/kg may blunt cardiac output and stroke volume and should be used with caution.

Epinephrine absorption following endotracheal administration: effects of hypoxia-induced low pulmonary blood flow.

To investigate the effects of hypoxia-induced decreased pulmonary blood flow on the trans-pulmonary absorption of epinephrine, we measured pulmonary blood flow and arterial plasma tritium counts per minute following endotracheal [3H]epinephrine administration in six chronically instrumented newborn lambs. The lambs were ventilated alternately with room air and with an hypoxic gas mixture sufficient to decrease pulmonary blood flow to approximately 50% of baseline values. Using this model, we found that hypoxia-induced low pulmonary blood flow did not lead to lower concentrations of epinephrine following endotracheal administration, but rather higher concentrations (P < 0.03). In all six lambs, counts per minute of tritium were higher following administration during low pulmonary blood flow. There was a negative correlation between pulmonary blood flow and arterial plasma tritium counts per minute (r = -0.64, P < 0.03). We conclude that trans-pulmonary absorption of epinephrine is not decreased during times of hypoxia-induced low pulmonary blood flow. These data lend support to the clinical practice of intratracheal epinephrine administration during neonatal resuscitation.

Meconium passage in very-low-birth-weight infants.

The timing of the first meconium stool has been considered a marker for proper gastrointestinal functioning in the term infant. There is limited information on the meconium passage patterns of very-low-birth-weight infants of less than 32 weeks' gestation. It is unknown whether feeding practices influence the timing of the first stool in these infants. We retrospectively studied 47 very-low-birth-weight infants with birth weights of 1250 g or less who were previously enrolled in a study of gastrointestinal (GI) priming. Infants whose mothers desired to breast feed (n = 7) were given GI priming with their own mother's milk. The remaining infants had been randomly assigned to receive total parenteral nutrition alone (n = 21) or GI priming with infant formula (n = 19) during the first 14 days of life. We attempted to advance all infants to full enteral nutrition by 21 days of age. There was no statistically significant difference in timing of the first stool among the three groups. The overall median age at first stool was 43 hours, and the 75th percentile was 10 days. The range was 1/2 hour to 27 days. There was no concordance between time of first stool and birth weight within the range studied. There was no concordance between time of first stool and necrotizing enterocolitis, although there was little statistical power to detect this. There was also very little concordance with feeding tolerance. Other than necrotizing enterocolitis, no significant GI disease developed in any of the infants studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Cocaine does not compromise cerebral or myocardial oxygen delivery in fetal sheep.

Eight time-dated pregnant ewes at 125 days' gestation (145 days = term) underwent surgery for placement of fetal vascular catheters, electrodes for recording fetal behavioural state, and maternal venous catheters. Three days later, fetal cerebral and myocardial blood flow were determined by the coloured microsphere technique under four conditions: (1) during rapid-eye movement (REM) sleep, before fetal cocaine infusion, (2) 30 min after initiation of a cocaine infusion to the fetus at 0.2 mg/kg per min, (3) during REM sleep, before maternal cocaine infusion, and (4) 30 min after initiation of a cocaine infusion to the ewe at 0.3 mg/kg per min. Cocaine infusion directly to the fetal lamb did not cause hypoxaemia or significantly change cerebral or myocardial blood flow or oxygen delivery. Cocaine administered to the ewe led to a drop in fetal oxygen tension from 3.0 +/- 0.5 to 2.5 +/- 0.3 kPa (P < 0.0001) and in fetal oxygen content from 3.8 +/- 0.7 to 2.8 +/- 0.4 mmol O2/L (P < 0.0001). Prior to maternal cocaine administration, fetal cerebral blood flow was 146 +/- 103 mL/100 g per min and during maternal cocaine infusion it went to 184 +/- 147 mL/100 g per min (P = NS) while myocardial blood flow increased from 156 +/- 92 to 333 +/- 178 mL/100 g per min (P < 0.002). This increase in blood flow negated the effects of hypoxaemia so that cerebral oxygen delivery was unaffected while myocardial oxygen delivery increased an average of 67%. It is concluded that cocaine administration to pregnant sheep does not impede fetal cerebral or myocardial oxygen delivery.

Accidental catheterization of internal iliac artery branches: a serious complication of umbilical artery catheterization.

Umbilical artery catheters can accidentally enter branches of the internal iliac artery during attempted placement in the aorta. The three branches likely to be catheterized are the superior gluteal, inferior gluteal, and internal pudendal arteries. If these misplacements are not recognized and promptly corrected, arterial obstruction may lead to ischemia and infarction of the iliac bone, gluteal muscles, sciatic nerve, perineum, and overlying skin. We present three patients who suffered long-term consequences of umbilical artery catheter misplacements and discuss the radiographic verification of catheter placement that is essential before infusing medications.

Term neonates with hemolytic disease of the newborn and necrotizing enterocolitis: a report of two cases.

Necrotizing enterocolitis in term infants is uncommon, and when it occurs it is usually associated with risk factors such as asphyxia, congenital heart disease, or polycythemia. It has been reported in term neonates after exchange transfusion for hemolytic disease of the newborn; therefore exchange transfusion is recognized as a risk factor. We report two term neonates with hemolytic disease of the newborn resulting from anti-c rhesus incompatibility in whom necrotizing enterocolitis developed before exchange transfusions. These cases implicate hemolytic disease of the newborn without exchange transfusion as a risk factor for necrotizing enterocolitis in term infants.

Accuracy of different methods for heart rate determination during simulated neonatal resuscitations.

OBJECTIVE: We hypothesized that during a simulated neonatal resuscitation, heart rate determination with the Neonatal Resuscitation Program's (NRP) 6-second method is difficult and results in inaccuracies. We tried to determine whether a simple electronic timing device improves accuracy of heart rate determination. METHODS: One-hundred fourteen clinicians determined four heart rates under conditions simulating a resuscitation by three different methods: their own method, NRP's 6-second method, and an electronic timing device method. Responses were scored as correct if they would have resulted in the same intervention as called for by NRP criteria for each specific heart rate tested. RESULTS: Of 1368 total responses, 267 (19.5%) were incorrect, which could have led to either an inappropriate intervention or lack of an appropriate intervention. The electronic timing device resulted in fewer errors (4%) compared with when clinicians used their own methods (32%) and the NRP's 6-second method (22%). CONCLUSION: The use of a simple electronic timing device improves accuracy of heart rate determination compared with the NRP's 6-second method or when clinicians use their own methods.

Multiple coronary thromboemboli and myocardial infarction in a newborn infant.

We report the case of a newborn infant with myocardial infarction caused by thromboembolic occlusion of the left main coronary artery. The clinical presentation was similar to that of hypoplastic left heart. This infant had no condition previously associated with perinatal myocardial infarction. Recognition and management of this rare condition, including the use of thrombolytic therapy, and the implication of deficient natural anticoagulant factors as a cause are discussed.

Medication use in neonatal resuscitation.

The American Heart Association has published guidelines for medication use in neonatal resuscitation. These recommendations should not, however, be regarded as standards or as the final word on resuscitation in neonates. Little work has been performed to justify these recommendations directly; therefore, it was necessary to make recommendations by extrapolating from studies not specifically designed to answer questions concerning the neonate. For example, the optimum dose of epinephrine administered either intravenously or endotracheally in a neonate with hemodynamically significant bradycardia is simply not known. The American Heart Association guidelines were made with reasoning based on the information available, even though the information is tangential. Similarly, since no data exist to document the benefit of NaHCO3 and some data would suggest harmful effects, its routine use is discouraged. Fertile areas for research exist to define better the optimum doses of epinephrine required in newborn resuscitation and to further delineate the importance and safety of rapid reversal of acidosis in newborn resuscitation.

Periviable birth: executive summary of a Joint Workshop by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Society for Maternal-Fetal Medicine, American Academy of Pediatrics, and American College of Obstetricians and Gynecologists.

This is an executive summary of a workshop on the management and counseling issues of women anticipated to deliver at a periviable gestation (broadly defined as 20 0/7 through 25 6/7 weeks of gestation), and the treatment options for the newborn. Upon review of the available literature, the workshop panel noted that the rates of neonatal survival and neurodevelopmental disabilities among the survivors vary greatly across the periviable gestations and are significantly influenced by the obstetric and neonatal management practices (for example, antenatal steroid, tocolytic agents and antibiotic administration; cesarean birth; and local protocols for perinatal care, neonatal resuscitation and intensive care support). These are, in turn, influenced by the variations in local and regional definitions of limits of viability. Because of the complexities in making difficult management decisions, obstetric and neonatal teams should confer prior to meeting with the family, when feasible. Family counseling should be coordinated with the goal of creating mutual trust, respect and understanding, and should incorporate evidence-based counseling methods. Since clinical circumstances can change rapidly with increasing gestational age, counseling should include discussion of the benefits and risks of various maternal and neonatal interventions at the time of counseling. There should be a plan for follow-up counseling as clinical circumstances evolve. The panel proposed a research agenda and recommended developing educational curricula on the care and counseling of families facing the birth of a periviable infant.

Prophylactic indomethacin infusion increases fractional cerebral oxygen extraction in ELBW neonates.

OBJECTIVE: Intraventricular hemorrhage (IVH) occurs in up to 25% of very low birth weight (VLBW) preterm neonates. Previous studies found that indomethacin administered in the first 6 h of life reduces the incidence of severe IVH in VLBW neonates and decreases cerebral blood flow, suggesting a decrease in cerebral oxygen delivery. Using near-infrared spectroscopy (NIRS), we monitored cerebral oxygenation before, during and after slow indomethacin infusion in extremely low birth weight (ELBW) neonates to determine whether indomethacin decreases cerebral oxygen saturation and increases cerebral oxygen extraction. STUDY DESIGN: Twenty-seven ELBW neonates less than 30 weeks gestational age treated with indomethacin for IVH prophylaxis were monitored for arterial oxygen saturation (SaO(2)) and NIRS-determined regional cerebral oxygen saturation (rSO(2)). At 30 to 60 s intervals, SaO(2), rSO(2) and mean arterial pressure (MAP) were recorded using a VitalSync. Average fractional cerebral oxygen extraction was calculated for the hour before indomethacin infusion, during the infusion and 2 h after infusion. RESULT: Fractional cerebral oxygen extraction increased from baseline after indomethacin administration from 0.23±0.11 to 0.25±0.10 (P=0.034). CONCLUSION: Fractional cerebral oxygen extraction increased 9% with indomethacin 0.1 mg kg(-1) given over 1 to 2 h. However, the clinical implications of this small increase in extraction, likely representative of decreased cerebral perfusion, are unknown but may be harmful to the developing brain.

The evaluation and management of postnatal thromboses.

In the pediatric population, neonates have the highest risk for thromboembolism (TE), most likely due to the frequent use of intravascular catheters. This increased risk is attributed to multiple risk factors. Randomized clinical trials dealing with management of postnatal thromboses do not exist, thus, opinions differ regarding optimal diagnostic and therapeutic interventions. This review begins with an actual case study illustrating the complexity and severity of these types of cases, and then evaluates the neonatal hemostatic system with discussion of the common sites of postnatal thrombosis, perinatal and prothrombotic risk factors, and potential treatment options. A proposed step-wise evaluation of neonates with symptomatic postnatal thromboses will be suggested, as well as future research and registry directions. Owing to the complexity of ischemic perinatal stroke, this topic will not be reviewed.